11-or 12-amino substituted quinolizines



United States Patent 11- OR 12-AMINO SUBSTITUTED QUINOLIZINES Robert J. Stanahack, Morristown, Richard E. Brown,

Hanover, and Robert I. Meltzer, Rockaway, N.J., as-

siguors to Warner-Lambert Pharmaceutical Company,

Morris Plains, N.J., a corporation of Delaware No Drawing. Filed Aug. 25, 1965, Ser. No. 482,607

4 Claims. (Cl. 260-288) This application is a continuation-in-part of application Ser. No. 451,306, filed Apr. 27, 1965.

This invention relates to novel 11- or IZ-amino substituted quinolizines of the formula:

wherein R and R may be hydrogen, hydroxy or lower alkoxy of 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy and the like or R and R taken together from a methylene dioxy group; R may be hydrogen or lower alkyl of l to 6 carbon atoms such as methyl, ethyl, propyl and the like; R may be hydrogen, -COOR or in which R, may be hydrogen or lower alkyl of l to 6 carbon atoms, acetyl or substituted acetyl such as in which R; may be hydroxy or acyloxy of l to 6 carbon atoms such as iormyloxy, acetoxy and the like; R may be hydrogen or an acyl or aroyl radical such as acetyl, propionyl, benzoyl and the like; R may be hydrogen, hydroxy or an acyloxy group of 1 to 6 carbon atoms such as formyloxy, acetoxy, and the like, or R and R taken taken together with the carbon atom to which they are attracted form a keto or cyclic ketal group, and n is an integer of from 1 to 2.

The compounds of this invention when n=2 have the following numbering system:

and when n=1 the numbering is as follows:

R R 3 1 I Lfa H-N\ l I 7 10 10b lf 9 Oa/\N/ 3 A B i 2 6a 5 The compounds of this invention exhibit significant pharmacological activity. For example, they are useful as cardiovascular agents, anti-inflammatory agents and for use in steroid therapy. In use, these compounds are combined with a non-toxic inert pharmaceutical carrier to form dosage forms such as tablets, capsules, elixirs, suppositories, suspensions, dispersible powders, and the like, the active ingredient being present in an amount from about 1 to 500 mg. per dosage unit.

These compounds may also be combined with other known therapeutic agents such as analgesics, for example, aspirin, codeine, cardiovascular agents such as pentaerythritoltetranitrate, glyceryltrinitrate, anti-inflammatory agents such as B-methasone-U-valerate or other steriods such as estrogens, progesterone and the like to enhance and broaden their pharmacological spectrum. In addi: tion, the compounds of this invention are useful as starting material for the production of compounds of the formula:

lower alkyl-O which may be produced by reaction with sodium in liquid ammonia as described by Birch in J. Chem. Soc. 1944.

The compounds of this invention are prepared by reducing the starting materials of the following formula:

L HO-N 3 aluminum hydride. When reductions are carried out vith those compounds in which there is a free ketone group present these ketone groups are protected by conersion to the corresponding cyclic ketal group through the lse of ethylene glycol prior to their reduction. The free etone group may be restored after the reduction by the we of mild acid hydrolysis.

In order to further illustrate the present invention, the Following examples are given:

EXAMPLE 1 1,2,3,3a,5,6,10b,11,12,I2a-decahydro-8-methoxy-II- aminbenz[a] -cycl0penta[f] quinolizine dihydrobromide A solution of 5.0 g. of 2,3,3a,5,6,11,12,12a-octahydrol-methoxy-l l-keto-lH benz[a]cyclopenta[f] quinolizinum chloride oxime in 100 ml. of acetic acid is hydrogenated over 0.1 g. of PtO catalyst at ambient temaerature and 50 p.s.i. hydrogen pressure. Hydrogen ab- :orption is complete after shaking for about 24 hours. The catalyst is removed by filtration. The solvent is 'emoved by distillation under reduced pressure. The gummy residue is dissolved in water and the solution is nade basic by the addition of 20% sodium hydroxide :olution. The precipitated has is extracted with methylene :hloride. The solution is dried and concentrated to a lCIl'll-SOlld- The base is taken up in 100 ml. of methanol 1nd dry hydrogen bromide is added. The solution is :oncentrated to dryness to give 1,2,3,3a,5,6,10b,11,12,12alecahydro 8 methoxy-11-arninobenz[a] cyclopenta jfJquinolizine dihydrobromide as a white solid, M.P. !7881 after recrystallization from ethanol.

EXAMPLE 2 l,2,3,3a,5,6,10b,11,12,12a decahydro 8 methoxy-IL amino-12a methyl 1 carbethoxybenz[a]cyclopenta [f] quinolizine dihydrobromide A solution of 0.5 g. of l,2,3a,5,6,l0b,l1,12,12a-decahydro-8-methoxy 11 keto l2a-methyl-l-carbethoxy- Jenz[a]cyclopenta[f]quinolizine oxime in 50 ml. of acetic acid containing 0.17 ml. of 72% perchloric acid is hydrogenated over 0.5 g. of PtO catalyst at ambient :emperature and 50 p.s.i. hydrogen pressure. Hydrogen absorption stops after about 3 hours. The catalyst is removed by filtration. The solvent is removed by distillation under reduced pressure. The residue is taken up in water and made basic by the addition of 20% sodium hydroxide solution. The precipitated base is extracted with ethyl acetate. The organic phase is dried, and dry hydrogen bromide is passed in. The precipitate is COOCaHi EXAMPLE 3 1,2,3,3a,5,6,10b,11,12,12a decahydro 8 methoxy-II- amino-12a methyl 1 carbethoxybenz[a]eyclopenta [f] quinolizine dihydrobromide H N j 1 MeO In the same way as described in Example 2, reduction of 0.5 g. of 2,3,3a,5,6,11,12,12a-octahydro 8 methoxy- 1l-keto-12a-methyl-1-carbethoxy 1H benz[a]cycl-openta[f]quinolizinium perchlorate oxime gives 1,2,3,3a,5, 6,l0b,11,12,l2-a decahydro 8 methoxy l1-amino- 12a methyl 1-carbethoxybenz[a]cyclopenta[f]quinolizine dihydrobromide as White crystals, M.P. 243-6 after recrystallization from ethanol.

It is to be understood that the foregoing detailed description is given merely by way of illustration and that many variations may be made therein without departing from the spirit of our invention.

Having described our invention, what we desire to secure by Letters Patent is:

1. A compound of the formula:

wherein R and R are each a member of the group consisting of hydrogen, hydroxy, lower alkoxy and R and R taken together form .a methylene dioxy group; R is a member of the group consisting of hydrogen methyl and ethyl; R is a member of the group consisting of hydrogen, COOR in which R is a member of the group consisting of lower alkyl and n is an integer of from 1 to 2.

2. 1,2,3,3a,5,6,10b,11,12,12a-decahydro 8 methoxy- 1 l-amino-benz [a] cyclopenta [f] quinolizine.

3. 1,2,3,3.a,5,6,10b,11,12,l2a-decahydro-8=methoxy-l1- aminobenz[a]cyclopenta[f] quinolizine dihydrobromide.

4. l,2,3,3a,5,6,10b,11,12,12a-decahydro-8-methoxy-1l amino 12a methyl-l-carbethoxybenz[a]cyclopenta[f] quinolizine dihydrobromide.

References Cited by the Examiner UNITED STATES PATENTS 2,982,775 5/1961 Oliveto et al 260397.45

ALEX MAZEL, Primary Examiner.

DONALD G. DAUS, Assistant Examiner. 

1. A COMPOUND OF THE FORMULA: 